CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort

Mannurita, Sara Ciullini; Vignoli, Marina; Bianchi, Lucia; Kondi, Anuela; Gerloni, Valeria; Breda, Luciana; Cate, Rebecca ten; Alessio, Maria; Ravelli, Angelo; Falcini, Fabio; Gambineri, Eleonora

doi:10.1038/ejhg.2013.123

Cited by 26 publications

(17 citation statements)

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“…The increase in age correlated significantly with the increased number of clinical findings (Spearman r = .8, p = 1.4 × 10 −07 ). We reviewed the literature and found 65 males and 41 females with CACP (male to female gender ratio = 1.6, binominal test p = .025) (Akawi, Ali, & Al‐Gazali, ; Alazami, Al‐Mayouf, Wyngaard, & Meyer, ; Albuhairan & Al‐Mayouf, ; Bahabri et al., ; Basit et al., ; Ciullini Mannurita et al., ; Faivre et al., ; Peters et al., )(Appendix c). In our cohort, we report 20 males with CACP and 15 females (males to female ratio = 1.3, binominal test p = .2).…”

Section: Resultsmentioning

confidence: 99%

“…Based on CACP mutation profiles, several authors previously stipulated that the syndrome is due to a complete lack of the protein PRG4 (Alazami et al., ; Basit et al., ; Ciullini Mannurita et al., ). In addition, studies using an antibody against the C‐terminal and N‐terminal of PRG4 protein showed its absence in CACP patient's synovial fluid, while it was detected in samples patients with rheumatoid arthritis and osteoarthritis (Ai et al., ).…”

Section: Discussionmentioning

confidence: 99%

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Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome

Yılmaz

Alkaya

Kasapçopur

et al. 2018

Molec Gen & Gen Med

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BackgroundThe camptodactyly–arthropathy–coxa vara–pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.MethodsIn the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.ResultsWe found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.ConclusionWith this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense‐mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome

Yılmaz

Alkaya

Kasapçopur

et al. 2018

Molec Gen & Gen Med

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“…Hyaline cartilage, a typical structure of cartilage in our body, plays a critical role in reducing friction and maintaining a wear-resistant property of articulating joint [ 1 ]. However, hyaline cartilage is easily damaged due to various causes such as injuries by repeated stress loading and degenerative joint diseases by natural aging or inflammatory activations [ 2 , 3 ]. Despite the susceptibility of impairment in hyaline cartilage, anatomical architecture that appears to have no vascular and lymphatic systems limits the native cartilage tissue regeneration [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of lubricin for functional cartilage tissue regeneration: a review

2018

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BackgroundLubricin is chondrocyte-secreted glycoprotein that primarily conducts boundary lubrication between joint surfaces. Besides its cytoprotective function and extracellular matrix (ECM) attachment, lubricin is recommended as a novel biotherapeutic protein that restore functional articular cartilage. Likewise, malfunction of lubrication in damaged articular cartilage caused by complex and multifaceted matter is a major concern in the field of cartilage tissue engineering.Main bodyAlthough a noticeable progress has been made toward cartilage tissue regeneration through numerous approaches such as autologous chondrocyte implantation, osteochondral grafts, and microfracture technique, the functionality of engineered cartilage is a challenge for complete reconstruction of cartilage. Thus, delicate modulation of lubricin along with cell/scaffold application will expand the research on cartilage tissue engineering.ConclusionIn this review, we will discuss the empirical analysis of lubricin from fundamental interpretation to the practical design of gene expression regulation.

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“…Currently, twenty-two mutations have been reported (HGMD professional 2015.3) [ 4 ]. It is predicted that all mutations will lead to a premature stop codon, resulting in the absence of functional lubricin [ 1 – 3 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The slow progressive onset of CACP syndrome can cause an initially incomplete clinical picture [ 7 ]. However, camptodactyly (85–100 %) and arthropathy (100 %) are found consistently [ 5 , 11 ]. Camptodactyly is symmetrical with a variable distribution.…”

Section: Introductionmentioning

confidence: 99%

Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome

et al. 2016

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BackgroundCamptodactyly-arthropathy-coxa vara-pericarditis (CACP, OMIM: #208250) syndrome is a rare autosomal recessive disease that can be difficult to recognise not only because of its wide clinical variability but also because of its clinical resemblance to juvenile idiopathic arthritis (JIA). PRG4 is the only gene so far known to be associated with CACP syndrome. Children with CACP syndrome lack the glycoprotein lubricin due to recessive mutations in PRG4. Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation. Children with CACP syndrome suffer from congenital camptodactyly, arthropathy, coxa vara and sometimes pericarditis. This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis and so contributes to knowledge of the presentation of CACP syndrome.Case PresentationA 10- year-old girl with consanguineous parents suffered from congenital camptodactyly and progressive swollen and painful joints. Her father and his sister had similar childhood-onset joint complaints. Laboratory tests showed no signs of inflammation but showed persistent low protein- and IgG- levels, indicating a secondary immunodeficiency. Increased alpha antitrypsin clearance confirmed PLE. Abdominal ultrasound with Doppler showed hepatomegaly and portal hypertension. Echocardiography suggested constrictive pericarditis. However, heart catheterization could not confirm this. Ultrasound and X-ray examination of the joints combined with a puncture of the synovial fluid were performed. These results, combined with the clinical presentation and the consanguinity, suggested CACP syndrome. Due to excessive enteral protein losses, the patient was treated with Cotrimoxazol prophylaxis and immunoglobulin supplements. These supplements were inadequate to achieve normal IgG values. As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results. Genetic testing in our patient was complicated but revealed a pathogenic mutation within the repeat sequence in exon 7 of the PRG4 gene.ConclusionPLE resulting from constrictive pericarditis can be a complication of CACP syndrome. As serious complications can arise from the resulting secondary immunodeficiency, we recommend regular evaluation of clinical symptoms of constrictive pericarditis and PLE in children with CACP syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0093-5) contains supplementary material, which is available to authorized users.

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CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort

Cited by 26 publications

References 23 publications

Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome

Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome

Regulation of lubricin for functional cartilage tissue regeneration: a review

Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome

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